July 23, 2016
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Mechanism of Action

Methylnaltrexone is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is restricted. This allows methylnaltrexone to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.


Effect on Cardiac Repolarization

In a randomized, double-blind placebo- and (open-label) moxifloxacin-controlled 4-period crossover study, 56 healthy subjects were administered methylnaltrexone bromide 0.3 mg/kg and methylnaltrexone bromide 0.64 mg/kg by intravenous infusion over 20 minutes, placebo, and a single oral dose of moxifloxacin. At both the 0.3 mg/kg and 0.64 mg/kg methylnaltrexone bromide doses, no significant effect on the QTc interval was detected.



Following subcutaneous administration, methylnaltrexone achieved peak concentrations (Cmax) at approximately 0.5 hours. Across the range of doses from 0.15 mg/kg to 0.50 mg/kg, mean Cmax and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner. There was no accumulation of methylnaltrexone following once-daily subcutaneous dosing of methylnaltrexone bromide 12 mg for seven consecutive days in healthy subjects.

Table 3: Pharmacokinetic Parameters of Methylnaltrexone Following Subcutaneous Doses

Parameter 0.15 mg/kg single dose 12 mg single dose 12 mg at steady-state
Cmax (ng/mL)i 117 (32.7) 140 (35.6) 119 (27.2)
tmax (hr)ii 0.5 (0.25-0.75) 0.25 (0.25-0.5) 0.25 (0.25-0.5)
AUC24 (ng·hr/mL) i 175 (36.6) 218 (28.3) 223 (28.2)
i Expressed as mean (SD).
iiExpressed as median (range).


The steady-state volume of distribution (Vss) of methylnaltrexone is approximately 1.1 L/kg. The fraction of methylnaltrexone bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis.


In a mass balance study, approximately 44% of the administered radioactivity was recovered in the urine over 24 hours with 5 distinct metabolites and none of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6-naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total) appear to be the primary pathways of metabolism. N-demethylation of methylnaltrexone to produce naltrexone is not significant.

After 12 mg once daily dosing the mean AUC0-24 ratio of metabolites to methylnaltrexone at steady-state was 30%, 19%, and 9% for methylnaltrexone sulfate, methyl-6α-naltrexol, and methyl-6β-naltrexol, respectively. Methyl-6α-naltrexol, and methyl-6β-naltrexol were active mu-opioid receptor antagonists and methylnaltrexone sulfate is a weak mu-opioid receptor antagonist.

Methylnaltrexone is conjugated by sulfotransferase SULT1E1 and SULT2A1 isoforms to methylnaltrexone sulfate. Conversion to methyl-6-naltrexol isomers is mediated by aldo-keto reductase 1C enzymes.


After intravenous administration, approximately half of the dose was excreted in the urine (53.6%) and 17.3% of administered dose was excreted in the feces up to 168 hours postdose. Methylnaltrexone is excreted primarily as the unchanged drug in the urine and feces. The terminal half-life (t½) is approximately 8 hours. Active renal secretion of methylnaltrexone is suggested by renal clearance of methylnaltrexone that is approximately 4-5 fold higher than creatinine clearance.

Specific Populations


A study was conducted to characterize the pharmacokinetics of methylnaltrexone after single dose of 24 mg methylnaltrexone via intravenous infusion over 20 min in healthy adults between 18 and 45 years of age and in healthy adults aged 65 years and older. In elderly subjects, mean clearance was about 20% lower (56 L/h versus 70 L/h) and AUC∞ was 26% higher than in subjects between 18 and 45 years of age.

Renal impairment

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone. Severe renal impairment decreased the renal clearance of methylnaltrexone by 8- to 9-fold and resulted in a 2-fold increase in total methylnaltrexone exposure (AUC). Mean Cmax was not significantly changed.

Hepatic impairment

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone has been studied in 8 subjects each, with Child-Pugh Class A and B, compared to healthy subjects. Results showed no meaningful effect of hepatic impairment on the AUC or Cmax of methylnaltrexone.

Drug Interactions

In vitro studies suggested that methylnaltrexone was a substrate of Organic Cation Transporter 1 but not a substrate of Organic Anion Transporter 1 or of P-glycoprotein.


A clinical drug interaction study in healthy adult subjects evaluated the effects of cimetidine, a drug that inhibits the active renal secretion of organic cations, on the pharmacokinetics of methylnaltrexone (24 mg administered as an IV infusion over 20 minutes). A single dose of methylnaltrexone was administered before cimetidine dosing and with the last dose of cimetidine (400 mg every 8 hours for 6 days). Mean Cmax and AUC of methylnaltrexone increased by 10% with concomitant cimetidine administration. The renal clearance of methylnaltrexone decreased about 40%.

Animal Toxicology and/or Pharmacology

In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone bromide caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 μM concentrations, respectively). Methylnaltrexone bromide had a hERG IC50 of > 1000 μM. In isolated dog Purkinje fibers, methylnaltrexone bromide caused prolongations in action potential duration (APD). The highest tested concentration (10 μM) in the dog Purkinje fiber study was about 18 and 37 times the Cmax at human subcutaneous (SC) doses of 0.3 and 0.15 mg/kg, respectively. In isolated rabbit Purkinje fibers, methylnaltrexone bromide (up to 100 μM) did not have an effect on APD, compared to vehicle control. The highest methylnaltrexone bromide concentration (100 μM) tested was about 186 and 373 times the human Cmax at SC doses of 0.3 and 0.15 mg/kg, respectively. In anesthetized dogs, methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at ≥ 1 mg/kg. In conscious dogs, methylnaltrexone bromide caused a dose-related increase in QTc interval. After a single intravenous dosage of 20 mg/kg to beagle dogs, predicted Cmax and AUC values were approximately 482 and 144 times, respectively, the exposure at human SC dose of 0.15 mg/kg and 241 times and 66 times, respectively, the exposure at a human SC dose of 0.3 mg/kg. In conscious guinea pigs, methylnaltrexone caused mild prolongation of QTc (4% over baseline) at 20 mg/kg, intravenous. A thorough QTc assessment was conducted in humans [see CLINICAL PHARMACOLOGY].

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions, tremors and labored breathing occurred at dosages of 3 and 10 mg/kg/day (about 3.2 and 11 times, respectively, the recommended human dose of 0.15 mg/kg based on the body surface area). Similar adverse clinical signs were seen in adult rats at 20 mg/kg/day (about 22 times the recommended human dose of 0.15 mg/kg based on the body surface area). Juvenile rats were found to be more sensitive to the toxicity of methylnaltrexone bromide when compared to adults. The no observed adverse effect levels (NOAELs) in juvenile and adult rats were 1 and 5 mg/kg/day, respectively (about 1.1 and 5.4 times respectively, the recommended human dose of 0.15 mg/kg based on the body surface area).

In juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks, juvenile dogs had a toxicity profile similar to adult dogs. Following intravenous administration of methylnaltrexone bromide for 13 weeks, decreased heart rate (13.2 % reduction compared to pre-dose) in juvenile dogs and prolonged QTc interval in juvenile (9.6% compared to control) and adult (up to 15% compared to control) dogs occurred at 20 mg/kg/day (about 72 times the recommended human subcutaneous doses of 0.15 mg/kg based on the body surface area). Clinical signs consistent with effects on the CNS (including tremors and decreased activity) occurred in both juvenile and adult dogs. The NOAELs in juvenile and adult dogs were 5 mg/kg/day (about 18 times the recommended human subcutaneous doses of 0.15 mg/kg based on the body surface area).

Clinical Studies

The efficacy and safety of RELISTOR in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose = 172 mg), and had opioid-induced constipation (either < 3 bowel movements in the preceding week or no bowel movement for > 2 days). Patients were on a stable opioid regimen ≥ 3 days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication.

Study 1 compared a single, double-blind, subcutaneous dose of RELISTOR 0.15 mg/kg, or RELISTOR 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label 4-week dosing period, where RELISTOR could be used as needed, no more frequently than 1 dose in a 24 hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR 0.15 mg/kg, 55 RELISTOR 0.3 mg/kg, 52 placebo) were enrolled and treated in the double-blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR-treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p < 0.0001 for each dose versus placebo (Figure 1).

Study 2 compared double-blind, subcutaneous doses of RELISTOR given every other day for 2 weeks versus placebo. Patients received opioid medication ≥ 2 weeks prior to receiving study medication. During the first week (days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR or placebo. In the second week the patient's assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient's assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR, 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR-treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p < 0.0001 (Figure 1). RELISTOR-treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p < 0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR.

Figure 1: Laxation Response Within 4 Hours of the First Dose

Laxation Response Within 4 Hours of the First Dose - Illustration

In both studies, there was no evidence of differential effects of age or gender on safety or efficacy. No meaningful subgroup analysis could be conducted on race because the study population was predominantly Caucasian (88%).

Durability of Response

Durability of response was explored in Study 2 and the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.

The efficacy and safety of methylnaltrexone bromide was also demonstrated in open-label treatment administered from Day 2 through Week 4 in Study 1, and in two open-label extension studies (Study 1EXT and Study 2EXT) in which RELISTOR was given as needed for up to 4 months. During open-label treatment, patients maintained their regular laxative regimen. A total of 136, 21, and 82 patients received at least 1 open-label dose in studies 1, 1EXT, and 2EXT, respectively. Laxation response was also explored in this open-label setting and appeared to be maintained over the course of 3 to 4 months of open-label treatment.

Opioid Use and Pain Scores

No relationship between baseline opioid dose and laxation response in methylnaltrexone bromide-treated patients was identified in exploratory analyses of these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either RELISTOR-treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either the methylnaltrexone bromide or placebo-treated patients.

Last reviewed on RxList: 9/19/2013
This monograph has been modified to include the generic and brand name in many instances.

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